U.S. patent number 4,806,534 [Application Number 06/921,397] was granted by the patent office on 1989-02-21 for therapeutically active flavonyl-1,4-dihydrophyridines.
This patent grant is currently assigned to Recordati S.A., Chemical & Pharmaceutical Company. Invention is credited to Pietro Cazzulani, Amedeo Leonardi, Dante Nardi, Renzo Pennini.
United States Patent |
4,806,534 |
Leonardi , et al. |
February 21, 1989 |
Therapeutically active flavonyl-1,4-dihydrophyridines
Abstract
The novel flavonyl-1,4-dihydropyridines having the general
formula (I): ##STR1## are therapeutically effective calcium
antagonists and smooth muscle relaxant.
Inventors: |
Leonardi; Amedeo (Milan,
IT), Pennini; Renzo (Milan, IT), Cazzulani;
Pietro (Milan, IT), Nardi; Dante (Milan,
IT) |
Assignee: |
Recordati S.A., Chemical &
Pharmaceutical Company (Chiasso, CH)
|
Family
ID: |
11198039 |
Appl.
No.: |
06/921,397 |
Filed: |
October 22, 1986 |
Foreign Application Priority Data
|
|
|
|
|
Oct 22, 1985 [IT] |
|
|
22578 A/85 |
|
Current U.S.
Class: |
514/233.5;
546/193; 546/271.4; 514/316; 514/337; 544/365; 546/269.7;
546/272.1; 546/275.4; 546/279.1; 546/274.7; 546/271.1; 546/283.1;
514/253.11; 514/232.5; 514/318; 544/131; 546/187 |
Current CPC
Class: |
C07D
231/12 (20130101); A61P 3/00 (20180101); C07D
249/08 (20130101); A61P 9/08 (20180101); A61P
9/10 (20180101); C07D 405/04 (20130101); A61P
3/14 (20180101); C07D 233/56 (20130101); C07D
211/90 (20130101) |
Current International
Class: |
C07D
211/00 (20060101); C07D 405/04 (20060101); C07D
405/00 (20060101); C07D 211/90 (20060101); C07D
521/00 (20060101); A61K 031/445 (); C07D
407/02 () |
Field of
Search: |
;546/269,187,193
;544/131,365 ;514/337,316,318,236,253 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
Thomas et al. J. of Cardiovasular Phar. 6: 1170-1176 1984. .
Schramm et al., Nature vol. 303. 9. Jun. 1983. .
Bossert et al. Angew. Chem. Int. Ed. Engl. 20, 762-769 (1981).
.
"Novel dihydropyridines with positive inotropic action through
activation of Ca.sup.2+ Channels," M. Schramm et al, Letters to
Nature vol. 303, Jun. 9, 1983. .
"Drug treatment of the overactive detrusor", K. E. Andersson et al,
Acta pharmacol, et toxicol. 1980, 46 Suppl. I, (7-11). .
"Effect of Calcium Channel Blockers on Urinary Tract Smooth
Muscle", Karl Brik Andersson et al, Acta Pharmacol Toxicol 58
(supple. II), 1986. .
"Anticholinergic and calcium antagonistic effects of terrodiline in
rabbit urinary bladder", S. Husted, et al, Acta Pharmacol. et
Toxicol 1980.46 (Suppl. I.) (20-30)..
|
Primary Examiner: Fan; Jane T.
Attorney, Agent or Firm: Burns, Doane, Swecker &
Mathis
Claims
What is claimed is:
1. A flavonyl-1,4-dihydropyridine having the formula: ##STR10## in
which: R and R.sub.1 are each independently selected from the group
consisting of alkyl having from 1 to 4 carbon atoms, hydroxyalkyl
having from 1 to 4 carbon atoms, formylalkyl and cyanoalkyl; and
R.sub.2 and R.sub.3 are each independently selected from the group
consisting of straight or branched chain alkyl having from 1 to 6
carbon atoms, straight or branched chain alkenyl having from 2 to 6
carbon atoms, alkynyl having from 2 to 6 carbon atoms, cycloalkyl
having from 5 to 7 carbon atoms, phenylalkyl, phenyl, cyanoalkyl,
haloalkyl, mono- or polyhydroxyalkyl, monoalkoxyalkyl,
alkylthioalkyl, alkylsulfonylalkyl, monoalkanoyloxyalkyl,
alkanoylalkyl, and R.sub.4 R.sub.5 N-straight or branched chain
alkyl; wherein R.sub.4 and R.sub.5 are each independently selected
from the group consisting of hydrogen, alkyl, cycloalkyl,
phenylalkyl, phenyl, and 3,3-diphenylpropyl, or wherein R.sub.4 and
R.sub.5 form together with their common nitrogen atom a 5- or
6-membered heterocycle optionally containing one other member
selected from the group consisting of O, S, N and NR.sub.6, in
which R.sub.6 is alkyl; or an optical isomer, a diasteromer or a
pharmaceutically acceptable salt thereof.
2. The flavonyl-1,4-dihydropyridine as defined by claim 1, wherein
at least one of R and R.sub.1 is an alkyl radical having from 1 to
4 carbon atoms.
3. The flavonyl-1,4-dihydropyridine as defined by claim 1, wherein
at least one of R and R.sub.1 is an hydroxyalkyl radical having
from 1 to 4 carbon atoms.
4. The flavonyl-1,4-dihydropyridine as defined by claim 1, wherein
at least one of R and R.sub.1 is a formyl(lower alkyl) radical.
5. The flavonyl-1,4-dihydropyridine as defined by claim 1, wherein
at least one of R and R.sub.1 is a cyano(lower alkyl) radical.
6. The flavonyl-1,4-dihydropyridine as defined by claim 1, wherein
at least one of R.sub.2 and R.sub.3 is a straight or branched chain
alkyl radical having from 1 to 6 carbon atoms.
7. The flavonyl-1,4-dihydropyridine as defined by claim 1, wherein
at least one of R.sub.2 and R.sub.3 is a straight or branched chain
alkenyl radical having from 2 to 6 carbon atoms.
8. The flavonyl-1,4-dihydropyridine as defined by claim 1, wherein
at least one of R.sub.2 and R.sub.3 is an alkynyl radical having
from 2 to 6 carbon atoms.
9. The flavonyl-1,4-dihydropyridine as defined by claim 1, wherein
at least one of R.sub.2 and R.sub.3 is a cycloalkyl radical having
from 5 to 7 carbon atoms.
10. The flavonyl-1,4-dihydropyridine as defined by claim 1, wherein
at least one of R.sub.2 and R.sub.3 is an lower aralkyl
radical.
11. The flavonyl-1,4-dihydropyridine as defined by claim 1, wherein
at least one of R.sub.2 and R.sub.3 is a phenyl radical.
12. The flavonyl-1,4-dihydropyridine as defined by claim 1, wherein
at least one of R.sub.2 and R.sub.3 is a cyano(lower alkyl)
radical.
13. The flavonyl-1,4-dihydropyridine as defined by claim 1, wherein
at least one of R.sub.2 and R.sub.3 is a halo(lower alkyl)
radical.
14. The flavonyl-1,4-dihydropyridine as defined by claim 1, wherein
at least one of R.sub.2 and R.sub.3 is a mono- or polyhydroxy(lower
alkyl) radical.
15. The flavonyl-1,4-dihydropyridine as defined by claim 1, wherein
at least one of R.sub.2 and R.sub.3 is a monohydroxy(lower alkyl)
radical.
16. The flavonyl-1,4-dihydropyridine as defined by claim 1, wherein
at least one of R.sub.2 and R.sub.3 is a lower alkylthio(lower
alkyl) radical.
17. The flavonyl-1,4-dihydropyridine as defined by claim 1, wherein
at least one of R.sub.2 and R.sub.3 is a lower alkylsulfonyl(lower
alkyl) radical.
18. The flavonyl-1,4-dihydropyridine as defined by claim 1, wherein
at least one of R.sub.2 and R.sub.3 is a mono(lower acyl)oxy(lower
alkyl) radical.
19. The flavonyl-1,4-dihydropyridine as defined by claim 1, wherein
at least one of R.sub.2 and R.sub.3 is a lower acyl(lower alkyl)
radical.
20. The flavonyl-1,4-dihydropyridine as defined by claim 1, wherein
at least one of R.sub.2 and R.sub.3 is an R.sub.4 R.sub.5 N-alkyl
radical, the alkyl moiety of which being straight or branched chain
and having from 2 to 6 carbon atoms, and in which R.sub.4 and
R.sub.5, which may be identical or different, are each hydrogen, or
a lower alkyl, lower cycloalkyl, lower alkyl, phenyl or
3,3-diphenylpropyl radical, with the proviso that R.sub.4 and
R.sub.5 may together form, with the nitrogen atom from which they
depend, a saturated or unsaturated heterocycle having from 4 to 7
ring members, and optionally containing one or more other O, S or N
heteroatoms, or a group NR.sub.6, in which R.sub.6 is a lower alkyl
radical.
21. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being dimethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
22. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being bis-2,N-piperidinoethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
23. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being isopropyl beta-chloroethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
24. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being isopropyl 2,N-piperidinoethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
25. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being isopropyl 2-(N-benzyl-N-methylamino)ethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
26. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being isopropyl 2-(N-(3,3-diphenylpropyl)-N-methylamino)ethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
27. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl 2-cyanoethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
28. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl ethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
29. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl 2-hydroxyethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
30. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl isopropyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
31. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl n-butyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
32. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl propargyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
33. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl allyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
34. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl alpha-methylallyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
35. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl benzyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
36. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl 2-oxopropyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
37. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl 2,3-dihydroxypropyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
38. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl 2-ethoxyethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
39. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl 2-ethylthioethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
40. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl 2-acetoxyethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
41. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl 2-phenylethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
42. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl 2-(N,N-dimethylamino)ethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
43. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl 2-aminoethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
44. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl 2-(N-methyl-N-phenylamino)ethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
45. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl 2-(N-methyl-N-cyclohexylamino)ethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
46. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl 2,N-morpholinoethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
47. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl 2,N-imidazolylethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
48. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl 2,N-piperidinoethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine
3,5-dicarboxylate.
49. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl 2,N-piperidino-1,1-dimethylethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
50. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl 2,N-methylaminoethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
51. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl 2,N-(N'-methyl)piperazinoethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
52. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl tert-butyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
53. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl cyclohexyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
54. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl phenyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
55. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being methyl 2-ethylsulfonylethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
.
56. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being dimethyl
2-formyl-6-methyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarbox
ylate.
57. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being dimethyl
2-hydroxymethyl-6-methyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-d
icarboxylate.
58. The flavonyl-1,4-dihydropyridine as defined by claim 1, the
same being dimethyl
2-cyano-6-methyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxy
late.
59. A composition of matter for eliciting a calcium-antagonistic or
smooth muscle relaxant response in a mammalian organism in need of
such treatment, comprising a therapeutically effective amount of
the flavonyl-1,4-dihydropyridine as defined by claim 1, and a
pharmaceutically acceptable carrier therefor.
60. A method of eliciting a calcium-antagonistic or smooth muscle
relaxant response in a mammalian organism in need of such
treatment, comprising administering to such organism a
therapeutically effective amount of the
flavonyl-1,4-dihydropyridine as defined by claim 1.
61. A method of eliciting a calcium-antagonistic or smooth muscle
relaxant response in a mammalian organism in need of such
treatment, comprising administering to such organism the
composition of matter as defined by claim 59.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel flavone compounds which are
useful calcium antagonists, as well as smooth muscle relaxants (in
particular, on the bladder), to processes for their preparation,
and to pharmaceutical compositions comprised thereof.
2. Description of the Prior Art
It is known to this art, from U.S. Pat. No. 2,921,070, that certain
ester of 3-methylflavon-8-carboxylic acid exhibit excellent
spasmolytic activity.
Moreover, it too is known to this art that a variety of compounds
having a 1,4-dihydropyridine basic nucleus, and substituted in the
3,5-positions by ester functions, display calcium-antagonistic
activity.
In German Pat. No. 3,311,005, for example, 1,4-dihydropyridine
derivatives are described which have chromone or thiochromone
substituents, but all are monoesters, bearing only hydrogen, or
nitro, cyano, halogen, alkyl, fluoroalkyl or hydroxycarbonyl
substituents at the 5-position of the dihydropyridine nucleus.
These particular compounds are disclosed as being useful
cardiotonic agents, to improve heart contractility, and as
anti-hypotonic agents, to lower blood sugar, for detumescing mucous
membranes, and to influence salt and liquid balance.
SUMMARY OF THE INVENTION
A major object of the present invention is the provision of a novel
class of 1,4-dihydropyridine/3-methylflavone compounds, which novel
compounds are important calcium antagonists and smooth muscle
relaxants (especially on the bladder).
Briefly, the novel compounds provided by this invention have the
general formula (I): ##STR2## wherein R and R.sub.1, which may be
identical or different, are each an alkyl radical having from 1 to
4 carbon atoms, a hydroxyalkyl radical having 1 to 4 carbon atoms,
or a formylalkyl or cyanoalkyl radical, and R.sub.2 and R.sub.3,
which also may be identical or different, are each a straight or
branched chain alkyl radical having from 1 to 6 carbon atoms, a
straight or branched chain alkenyl radical having from 2 to 6
carbon atoms, an alkynyl radical having from 2 to 6 carbon atoms, a
cycloalkyl radical having from 5 to 7 carbon atoms, an aralkyl
radical, a phenyl radical, a cyanoalkyl radical, a haloalkyl
radical, a mono- or polyhydroxyalkyl radical, a monoalkyloxyalkyl
radical, an alkylthioalkyl radical, an alkylsulfonylalkyl radical,
a monoacyloxyalkyl radical, an acylalkyl radical, or an R.sub.4
R.sub.5 N-alkyl straight or branched chain radical having from 2 to
6 carbon atoms, in which R.sub.4 and RHD 5, which may be identical
or different, are each hydrogen, an alkyl radical, a cycloalkyl
radical, an aralkyl radical, a phenyl radical, a 3,3-diphenylpropyl
radical, or, alternatively, together with the nitrogen atom from
which they depend, a saturated or unsaturated heterocyclic ring
having from 4 to 7 ring members, and optionally containing one or
more other heteroatoms, such as O, N or S, or an NR.sub.6 radical,
in which R.sub.6 is an alkyl radical. This invention also features
the optical isomers and diasteroisomers of the compounds (I), as
well as the pharmaceutically acceptable salts thereof.
Advantageously, the various alkyl, alkoxy and acyl moieties of the
aforesaid combination radicals are lower alkyl, lower alkoxy and
lower acyl moieties having up to about 8 carbon atoms.
Preferably at least one of R or R, comprises an alkyl radical
having 1 to 4 carbon atoms, a hydroxyalkyl radical having 1 to 4
atoms, a formyl(lower alkyl) radical, or a cyano (lower alkyl)
radical. Further preferred embodiments are where at least one of
R.sub.2 or R.sub.3 comprise a straight or branched chain alkyl
radical having from 1 to 6 carbon atoms, a straight or branched
chain alkenyl radical having 2 to 6 carbon atoms, a R.sub.2 or
R.sub.3 alkynyl radical having 2 to 6 carbon atoms, a cycloalkyl
radical having 5 to 7 carbon atoms, an ar(lower alkyl) radical, a
phenyl radical, a cyano(lower alkyl) radical, a halo(lower alkyl)
radical, a mono-or polyhydroxy(lower alkyl) radical, a
monohydroxy(lower alkyl) radical, a lower alkylthio(lower alkyl)
radical, a lower alkylsulfonyl(lower alkyl)radical, a mono(lower
acyl)oxy(lower alkyl) radical, a lower acyl(lower alkyl) radical,
or an R.sub.4 R.sub.5 N-alkyl radical, the alkyl moiety of which
being straight or branched chain and having from 2 to 6 carbon
atoms, and in which R.sub.4 and R.sub.5, which may be identical or
different, are each hydrogen, or a lower alkyl, lower cycloalkyl,
lower aralkyl, phenyl or 3,3-diphenylpropyl radical, with the
proviso that R.sub.4 and R.sub.5 may together form, with the
nitrogen atom from which they depend, a saturated or unsaturated
heterocycle having from 4 to 7 ring members, and optionally
containing one or more other O, S or N heteroatoms, or a group
NR.sub.6, in which R.sub.6 is a lower alkyl radical.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE
INVENTION
More particularly according to the present invention, the subject
compounds having the formula (I) are conveniently prepared, either
by:
(a) reacting an aldehyde having the formula (II): ##STR3## with a
ketoester having the formula (III): ##STR4## and with an enamine
having the formula (IV): ##STR5## wherein R, R.sub.1, R.sub.2 and
R.sub.3 are as defined above, and in which R, R.sub.1 may facilely
be transformed by known procedures into, e.g., formylalkyl,
hydroxyalkyl, or cyanoalkyl radicals, or, alternatively:
(b) by treating an aldehyde (II) with a compound having the formula
(V): ##STR6## wherein R.sub.1 is defined as in (a) and X is a
halogen atom, and reacting the arylidene derivative thus formed
with an enamine having the formula (VI): ##STR7## wherein R and
R.sub.2 are as defined above, and optionally adding an amine of the
formula R.sub.4 R.sub.5 NH, wherein R.sub.4 and R.sub.5 are as
above defined, or alternatively:
(c) reacting an aldehyde (II) with a ketoester having the formula
(III) and then adding to the resulting arylidene derivative an
enamine having the formula (VII): ##STR8## wherein R, R.sub.1 and
R.sub.2 are as above defined, or defined under (a), further
hydrolyzing the 1,4-dihydropyridinic cyanoethylester thus formed to
give the acid having the formula (VIII): ##STR9## and then
esterifying (VIII), following known procedures, with a compound of
the formula R.sub.3 OH or R.sub.3 X, in which X is a halogen atom
and R.sub.3 is as defined above.
The reaction of scheme (a) is typically carried out in a lower
alcohol, at the reflux temperature of the alcohol used, for a
period of 2-5 hours. Ethanol is the preferred alcohol. After
cooling and standing, the precipitated material is isolated in
usual manner and optionally purified by recrystallization.
The reaction between (II) and (V) in the scheme (b) is typically
carried out in a chlorinated hydrocarbon, preferably chloroform,
whereas the further addition of (VI) is in a lower alcohol,
preferably isopropanol. The optional further reaction with the
amine of the formula R.sub.4 R.sub.5 NH is carried out in
dimethylformamide, under stirring, at a temperature of about
100.degree. C.
The reaction of scheme (c) is carried out, in the first step, in
chloroform; the subsequent addition of the enamine (VII) is in
alcohol (isopropanol), the hydrolysis of the cyanoethylester is in
dimethoxyethane and, finally, the esterification of the acid thus
obtained is in dimethylformamide.
The transformation of R or R.sub.1 into a formylalkyl radical is
carried out by cyclization of a compound of the formula (VII) or
(III), in which R or R.sub.1 is geminal dialkoxyalkyl, and then by
hydrolysis, with hydrochloric acid in acetone, of the resultant
1,4-dihydropyridinic ring of the formula (I), having in R or
R.sub.1 the aforesaid dimethoxyalkyl group.
The formalkyl radical can be reduced to the corresponding
hydroxyalkyl radical using sodium borohydride in ethanol, or,
alternatively, can be converted into the corresponding cyanoalkyl
group, by means of hydroxylamine and acetic anhydride.
For more details on the aforesaid reaction schemes for the
preparation of the compound (I), see the working examples to
follow.
All of the intermediates of the formulae (III)-(VIII) are known
compounds, or can easily be prepared following known
procedures.
The salts according to the invention may be prepared from the basic
esters obtained as described above according to conventional
methods, such as addition of an acid to the free base dissolved in
a suitable solvent. Suitable acids include hydrogen halides,
phosphoric acid, nitric acid, alkylsulfonic acids, arylsulfonic
acids, monofunctional and bifunctional carboxylic acids,
hydroxycarboxylic acids and 1,5-naphthalenedisulfonic acid, and
isolation and purification may be effected conventionally.
The novel compounds having the general formula (I) display marked
calcium-antagonistic activity and/or a relaxing activity on smooth
musculature (in particular, on the musculature of the bladder) and,
moreover, are characterized by low toxicity.
Thus, the present invention also features pharmaceutical
compositions containing, as active constituent thereof, a compound
of the formula (I), together with the usual carriers, supports and
diluents. The formulations can be in the form of tablets, capsules,
pills, granulates, syrups, emulsions, suspensions and solutions,
and are prepared in usual manner by mixing the active substances
with solvents and/or carriers, optionally adding emulsifying agents
and/or dispersants; whenever water is used as the diluent, organic
solvents can also be used as adjuvants. Administration thereof is
in usual manner, preferably per oral or by parenteral route. In the
case of oral administration, the pharmaceutical forms suitable for
this purpose can also contain additives, as well as various
supplementary materials, such as starch, gelatin or the like. In
the case of liquid forms, compatible colorants, or taste-correcting
materials can be added. For parenteral administration, solutions of
the active agent are added with the usual liquid excipients well
known to those skilled in this art.
The novel compounds according to the present invention inhibit the
receptor binding of .sup.3 H-nitrendipine, thus demonstrating
calcium-antagonistic activity. They augment the bladder capacity
and reduce the micturition pressure and the contractility of the
detrusor muscle in addition to having very low toxicity. From tests
performed on rats, it has been shown that in order to elicit
optimal activity in relaxing the smooth musculature of the bladder,
it is generally advisable to administer the subject compounds per
oral route.
The LD.sub.50 of the novel compounds of the invention was
determined in mice, both i.p. and p.o., following the method
described by C. S. Weil, Biometrics, 8, 249 (1952). Exemplary
results are reported in Table 1.
TABLE 1 ______________________________________ LD.sub.50 mg/kg
(mice) Active compound i.p. p.o.
______________________________________ i 889 >3000 iii >1000
>3000 iv 222 >3000 v 959 >3000 vi >1000 >3000 viii
>1000 >3000 xii 597 >3000
______________________________________
The activity on calcium-antagonistic binding site was detected "in
vitro" by displacement of .sup.3 H-nitrendipine, according to the
method of Bolger et al, J. Pharm. Exp. Ther., 225, 291 (1983).
For the binding assays, rat brain membranes were used, the reaction
mixture (2 ml) was incubated for 60 minutes at 25.degree. C.
together with .sup.3 H-nitrendipine (0.45 nM) and various
concentrations of the tested compound. IC.sub.50 's values were
determined from inhibition curves derived from the binding of the
.sup.3 H-nitrendipine to its respective binding site in the
presence of the antagonist compound, and calculated
nonlinearly.
Exemplary results are reported in Table 2.
TABLE 2 ______________________________________ Activity on
calcium-antagonistic binding site (rat) Active compound IC.sub.50
(nM) ______________________________________ i 5.55 10.sup.-9 iii
8.81 10.sup.-9 iv 3.03 10.sup.-7 v 8.36 10.sup.-9 vi 1.30 10.sup.-7
viii 3.06 10.sup.-9 x 1.35 10.sup.-8 xi 5.45 10.sup.-8 xii 3.19
10.sup.-8 xiv 1.46 10.sup.-8 xvi 3.96 10.sup.-9 xviii 1.66
10.sup.-8 xx 4.91 10.sup.-8
______________________________________
By IC.sub.50 is intended the concentration of a compound which
reduces specific binding of .sup.3 H-nitrendipine to 50% of its
maximal value.
The activity on the urodynamic parameters was detected by
cystometric recordings, carried out in conscious rats, according to
the method of Pietra et al, IRCS Medicinal Science, in press
(1986), similar to that described by Sjogren, Acta Pharmacol.
Toxicol., 39, 177 (1976). The intravesical pressure was recorded
during a continuous infusion of saline (37.degree. C.) into the
urinary bladder at the constant rate of 0.15 ml/min. The bladder
volume capacity (BVC), and micturition pressure (MP), were recorded
before and after administration of the compounds per oral route.
The perfusion started 60 minutes after administration of the
compound.
Exemplary results obtained are reported in Table 3, wherein BVC is
the bladder volume capacity, and MP is the micturition
pressure.
TABLE 3 ______________________________________ Cystometric
recordings (rat) Active Dose compound (mg/kg p.o.) % Change BVC %
Change MP ______________________________________ i 10 +18 -14 30
+21 -19 iii 30 +15 -1 v 10 +19 -16 30 +22 -23 vi 30 +31 -1
______________________________________
In order to further illustrate the present invention and the
advantages thereof, the following specific examples are given, it
being understood that same are intended only as illustrative and in
nowise limitative.
EXAMPLE 1
Preparation of 3-methyl-8-formylflavone (II)
A mixture of 59.74 g of 3-methyl-8-chlorocarbonylflavone (obtained
from 3-methylflavon-8-carboxylic acid and thionyl chloride, white
crystals, m.p. 156.degree.-156.5.degree. C.), 200 ml of xylene, 6 g
of 5% palladium on barium sulfate and 0.4 ml of quinoline-S,
maintained under stirring and under hydrogen flow, was heated for
6-7 hours at 85.degree.-90.degree. C. Upon completion of the
reaction, the mixture was cooled, diluted with chloroform (20 ml),
filtered, the solvent was evaporated under vacuum, and 260 ml of
20% sodium hydrogensulfite (W/V) and 600 ml of water were added to
the residue. The mixture thus obtained was heated at reflux for 2
hours and then filtered while hot. The cooled filtrate was
extracted several times with ethyl ether (4.times.200 ml),
concentrated hydrogen chloride added and then heated to
95.degree.-100.degree. C. for 2 hours. After cooling, the solid
thus formed was filtered and washed with water. The product (II)
was obtained in a global yield equal to 78% of theoretical (41.46
g) and could be used as such in further syntheses. After
recrystallization from methyl-tert-butyl-ether, it melted at
124.degree.-126.degree. C.
Procedural scheme (a)
Dimethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(i)
A mixture of 7.94 g of 3-methyl-8-formylflavone (obtained as
described above), 4.1 g of methyl acetoacetate, 4.14 g of methyl
3-aminocrotonate and 22.5 ml of ethanol was heated at reflux in the
dark and under stirring for 4 hours. After cooling to room
temperature, the mixture was maintained overnight at 5.degree. C.,
then the insoluble fraction thus obtained was filtered, washed with
ice-cooled ethanol (3.times.5 ml) and crystallized, first from
ethanol and then from methanol until constant m.p.
(245.degree.-249.degree. C.). By concentration of the liquors of
crystallization, an additional 5.33 g of product were obtained
which, combined with the 4.05 g previously obtained, increased the
global yield of the title compound to 9.38 g.
Bis-2,N-piperidinoethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(ii)
This compound, melting at 210.degree.-216.degree. C. after
crystallization from acetonitrile/ethyl acetate, was prepared
following the procedure described above, but using, instead of
methyl acetoacetate and methyl 3-aminocrotonate,
2,N-piperidinoethyl acetoacetate and 2,N-piperidinoethyl
3-aminocrotonate (prepared following usual procedures).
EXAMPLE 2
Procedural scheme (b)
Step 1
Preparation of beta-chloroethyl
2-(3-methylflavon-8-methyliden)acetoacetate
A mixture of 52.8 g of (II), 32.84 g of
beta-chloroethylacetoacetate and 400 ml of toluene was saturated at
0.degree./+5.degree. C. with gaseous hydrochloric acid. The mixture
was permitted to stand at room temperaure for 24-48 hours, then
nitrogen was bubbled therethrough to expel the acid and the solvent
was evaporated. The residue was washed first with hot ethyl ether
(2.times.100 ml) and then with cold ethyl ether (1.times.100 ml) to
obtain 70 g of the title compound as the sole stereoisomer, melting
at 130.degree.-131.degree. C.
STEP 2
Isopropyl beta-chloroethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(iii)
A mixture of 51.35 g of the aforedescribed acetoacetate and 7.15 ml
of isopropyl 3-aminocrotonate in 94 ml of isopropanol, maintained
under stirring and protected from light, was heated to 80.degree.
C. for 2 hours. After cooling, the solid precipitae thus formed was
separated by filtration and washed with isopropanol (3.times.30 ml)
to obtain 53 g of the title compound that was used as such for
further reactions.
A sample, crystallized from acetone for elemental analysis, melted
at 235.degree.-237.degree. C.
Step 3
Isopropyl 2,N-piperidinoethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(iv)
A mixture of the above compound and 2.13 g of piperidine in 20 ml
of anhydrous dimethylformamide, maintained under stirring, under a
nitrogen atmosphere and in the dark was heated at 100.degree. C.
for 3 hours, then cooled and poured into 100 ml of ice-cold water.
The solid precipitate thus formed was filtered, washed with water
and, after drying, chromatographed on a silica-gel column (ethyl
acetate/methanol (9:1) as eluent). After evaporation of the
solvent, the title compound was obtained as residue. The yield was
2.92 g, after crystallization from ethyl acetate, m.p.
205.degree.-206.degree. C.
Following the procedure of Step 3 of this Example, but using
N-methylbenzylamine instead of piperidine, isopropyl
2-(N-benzyl-N-methylamino)ethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(v) was obtained, melting at 170.degree.-172.degree. C.
(ethanol).
In the same manner, but employing N-methyl-3,3-diphenylpropylamine
instead of piperidine, isopropyl
2-(N-(3,3-diphenylpropyl)-N-methylamino)ethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
was obtained (vi), melting at 151.degree.-153.degree. C.
(ethanol).
EXAMPLE 3
Procedural scheme (c)
Step 1
Preparation of methyl
2-(3-methylflavon-8-methyliden)acetoacetate
Following the procedure described in Step 1 of Example 2 for the
preparation of beta-chloroethyl
2-(3-methylflavon-8-methyliden)acetoacetate, but starting from a
solution comprising 39.6 g of (II) and 17.4 g of methylacetate in
150 ml of chloroform, the title compound was prepared (38.55
g).
STEP 2
Methyl 2-cyanoethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(vii)
Following the procedure described in Step 2 of Example 2, but using
a mixture of 36.2 g of the above acetoacetate and 15.42 g of
2-cyanoethyl 3-aminocrotonate in 60 ml of isopropanol, 42 g of the
title compound were prepared and used for the subsequent reaction
without further purification. A sample, crystallized from
methylenechloride/ethyl ether for elemental analysis, melted at
190.degree.-192.degree. C.
Step 3
Preparation of
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylic
acid monomethylester hydrate
To a solution of 25 g of the 2-cyanoethyl derivative above
described, in 250 ml of dimethoxyethane maintained at
20.degree.-25.degree. C. under stirring and in the dark were added
dropwise, first, 150 ml of water and then 100 ml of 1N sodium
hydroxide. The mixture was maintained at the same temperature for
about 2 hours, then was extracted with chloroform (2.times.6.5 ml)
and then with ethyl ether (1.times.6.5 ml). The aqueous phase was
added to ice and acidified to pH 2-3 with hydrochloric acid, and
the precipitate thus formed was filtered, washed, dried and
crystallized from methanol to give 11.67 g of the title compound,
melting at 159.degree.-160.degree. C.
Step 4
Methyl ethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(viii)
A mixture of 9.26 g of the acid prepared as described above, 4.6 g
of dicyclohexylcarbodiimide, 0.24 g of 4-N,N-dimethylaminopyridine
and 9.2 ml of ethanol in 40 ml of anhydrous dimethylformamide,
maintained under stirring in the dark and under a nitrogen
atmosphere, was heated at 80.degree. C. for 24 hours. Upon
completion of the reaction, after cooling, the mixture was filtered
and the filtrate was poured into 200 ml of ice-cold water. The
precipitate thus formed was collected on a filter, washed with
water, dried and crystallized from ethanol, to give 6.4 g of the
title compound, melting at 226.degree.-228.degree. C.
Following the procedure described in the above Step 4, but starting
from 0.92 g of the acid described in Step 3, and employing 0.3 g of
bromoethanol and 0.276 g of anhydrous potassium carbonate instead
of dicyclohexylcarbodiimide and the 4-N,N-dimethylaminopyridine,
0.33 g of methyl 2-hydroxyethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(ix) were obtained, melting at 201.degree.-203.degree. C.
In the same manner, but employing a suitable halogen-derivative
instead of bromoethanol, the following compounds were prepared:
Methyl isopropyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(x) (m.p. 209.degree.-211.degree. C.);
Methyl n-butyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xi) (m.p. 196.degree.-198.degree. C.);
Methyl propargyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xii) (m.p. 213.degree.-216.degree. C.);
Methyl allyl
2,6-dimethyl-4-(3-methylflavon-8yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xiii) (m.p. 219.degree.-221.degree. C.);
Methyl alpha-methylallyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xiv) (m.p. 187.degree.-192.degree. C.);
Methyl benzyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xv) (m.p. 204.degree.-207.degree. C.);
Methyl 2-oxopropyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xvi) (m.p. 182.degree.-183.degree. C.);
Methyl 2,3-dihydroxypropyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xvii) (m.p. 168.degree.-170.degree. C.);
Methyl 2-ethoxyethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xviii) (m.p. 188.degree.-191.degree. C.);
Methyl 2-ethylthioethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xix) (m.p. 165.degree.-167.degree. C.);
Methyl 2-acetoxyethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xx) (m.p. 183.degree.-186.degree. C.);
Methyl 2-phenylethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xxi) (m.p. 196.degree.-199.degree. C.);
Methyl 2-(N,N-dimethylamino)ethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xxii) (m.p. 208.degree.-210.degree. C.).
EXAMPLE 4
Methyl 2-aminoethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xxiii)
To a suspension of 5.34 g of the acid prepared as described in Step
3 of Example 3, in 24 ml of anhydrous methylene chloride and 6 ml
of anhydrous dimethylformamide maintained under stirring and under
a nitrogen atmosphere at --5.degree./0.degree. C., 1.64 g of
thionyl chloride were added dropwise, over 5 minutes, and
thereafter 1.35 g of 2-aminoethanol hydrochloride were added
dropwise, over 30 minutes, at 0.degree./5.degree. C. After standing
for 3 hours at 20.degree.-25.degree. C., the mixture was cooled
again on an ice-cold bath and 50 ml of 10% sodium carbonate were
added dropwise. The organic phase was separated and washed with
water (1.times.30 ml), with 25% acetic acid (V/V) and then with
(2.times.60 ml) of water. The acidic and aqueous layers were
combined, washed with ethyl ether (2.times.60 ml) and alkalinized
with concentrated sodium hydroxide. After standing, the precipitate
was collected, washed with water, dried and purified by silica-gel
chromatography, eluting with a mixture of ethyl
acetate/methanol/methanolic ammonia (about 7.5N) in a ratio of
92:8:4. 3.81 g of the title compound, melting at
188.degree.-192.degree. C., were obtained after crystallization
from methylene chloride/ethyl ether.
Following the procedure described above, but employing a suitable
alcohol instead of 2-aminoethanol, the following compounds were
obtained:
Methyl 2-(N-methyl-N-phenylamino)ethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xxiv) (m.p. 177.degree.-182.degree. C.);
Methyl
2-(N-methyl-N-cyclohexylamino)ethyl)2,6-dimethyl-4-(3-methylflavon-8-yl)-1
,4-dihydropyridine-3,5-dicarboxylate (xxv) (m.p.
153.degree.-155.degree. C.);
Methyl 2,N-morpholinoethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xxvi) (m.p. 215.degree.-217.degree. C.);
Methyl 2,N-imidazolylethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xxvii) (m.p. 198.degree.-200.degree. C.);
Methyl 2,N-piperidinoethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xxviii) (m.p. 189.degree.-193.degree. C.);
Methyl 2,N-piperidino-1,1-dimethylethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xxix) (m.p. 212.degree.-214.degree. C.);
Methyl 2,N-methylaminoethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xxx) (m.p. 180.degree.-182.degree. C.);
Methyl 2,N-(N'-methyl)piperazinoethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xxxi) (m.p. 181.degree.-185.degree. C.);
Methyl tert-butyl
2,6-dimethyl-4-(3-methylflavon-8yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xxxii) (m.p. 222.degree.-225.degree. C.);
Methyl cyclohexyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xxxiii) (m.p. 137.degree.-139.degree. C.);
Methyl phenyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xxxiv) (m.p. 211.degree.-213.degree. C.);
Methyl 2-ethylsulfonylethyl
2,6-dimethyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(xxxv) (m.p. 195.degree.-200.degree. C.).
EXAMPLE 5
Step 1
Preparation of methyl
4,4-dimethoxy-2-(3-methylflavon-8-methyliden)acetoacetate
A mixture comprising 2.64 g of (II), 2.1 g of methyl
4,4-dimethoxyacetoacetate, 0.034 ml of acetic acid, 0.038 ml of
piperidine and 8 ml of benzene, was heated to reflux under stirring
for 12 hr, while the azeotropic mixture was distilled off. After
cooling, the solution was first washed with 5% sodium bicarbonate,
then with water, and dried over anhydrous sodium sulfate. After
evaporation of the solvent, the residue was purified by silica-gel
chromatography, eluting with petroleum ether/ethyl acetate first in
a 4:1 ratio and then in a 3:2 ratio. The fractions containing the
pure product were collected and the solvents were evaporated to
give 2 g of the title compound that was used for the subsequent
reaction without further purification.
A sample, crystallized from ethyl acetate adding petroleum ether,
melted at 124.degree.-126.degree. C.
Step 2
Dimethyl
2-dimethoxymethyl-6-methyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5
-dicarboxylate (xxxvi)
A mixture of 1.1 g of the acetoacetate described in the above step,
0.34 g of methyl 3-aminocrotonate and 1.5 ml of
N,N-dimethylformamide, maintained under nitrogen atmosphere in the
dark, was heated at 80.degree. C. under stirring for 5 hr and then
at 100.degree.-105.degree. C. for an additional 7 hr. After
cooling, the mixture was diluted with about 15 ml of water and
extracted with ethyl ester. The organic phase was washed with
water, dried over sodium sulfate and, after evaporation of the
solvent, the residue was purified by silica-gel chromatography,
eluting with ethyl ether. The fractions containing the pure product
were collected and, after evaporation of the solvent, the residue
was crystallized from ethyl acetate adding petroleum ether, to give
0.32 g of the title compound, melting at 166.degree.-168.degree.
C.
Step 3
Dimethyl
2-formyl-6-methyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarbox
ylate (xxxvii)
A solution of 10.15 g of the dimethoxymethyl derivative, obtained
as described in the above Step 2, in 88 ml of acetone and 10 ml of
6N hydrochloric acid, was stirred under nitrogen atmosphere and in
the dark for 5 hr at 18.degree.-22.degree. C. After dilution with
120 ml of water, 5.04 g of sodium bicarbonate were added
portionwise and then most of the acetone was evaporated off, and
the solids collected by filtration were purified by silica-gel
chromatography, eluting with methylene chloride/ethyl ether (9:1).
The fractions containing the pure compound were collected and,
after evaporation of the solvent, the residue was crystallized from
acetonitrile to give 4.6 g of the title compound, melting at
216.degree. C.
EXAMPLE 6
Dimethyl
2-hydroxymethyl-6-methyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-d
icarboxylate (xxxviii)
To a mixture comprising 3.3 g of the 2-formyl derivative prepared
as described in Step 3 of the previous Example, 52 ml of ethanol,
18 ml of methylene chloride, maintained under stirring at 0.degree.
C., under a nitrogen atmosphere and in the dark, 0.28 g of sodium
borohydride was added portionwise. The solution was maintained
under these conditions for 2 hr, then was acidified with 50% acetic
acid, most of the solvents were evaporated under vacuum and to the
residue were first added 70 ml of water and then 5% of sodium
bicarbonate, until the reaction mixture was alkaline. The solids
thus formed were collected by filtration and crystallized from
acetonitrile to give 1.7 g of the title compound, melting at
231.degree.-233.degree. C.
EXAMPLE 7
Dimethyl
2-cyano-6-methyl-4-(3-methylflavon-8-yl)-1,4-dihydropyridine-3,5-dicarboxy
late (xxxix)
A mixture comprising 0.95 g of the 2-formyl derivative prepared as
described in the previous Example, 0.17 g of hydroxylamine
hydrochloride, 0.245 g of anhydrous sodium acetate and 3.7 ml of
acetic acid, was maintained under stirring at 18.degree.-22.degree.
C. in the dark and under a nitrogen atmosphere for 4 hr.
Thereafter, 0.75 g of acetic anhydride was added, and the mixture
was adjusted to 18.degree.-22.degree. C. for 1 hr, and then heated
to 95.degree.-100.degree. C. for 4 hr. After cooling, most of the
acetic acid was evaporated under vacuum, and the residue was
diluted with waer, neutralized with 5% sodium bicarbonate and then
extracted with ethyl acetate. The crude material obtained after
evaporation of the organic phase was purified by silica-gel
chromatography, eluting with methylene chloride/ethyl acetate
(9:1). The fractions containing the pure compound were collected,
the solvents were evaporated and the residue crystallized from
N,N-dimethylformamide/water to give 0.3 g of the title compound,
melting at about 250.degree. C.
While this invention has been described in terms of various
preferred embodiments, the skilled artisan will appreciate that
various modifications, substitutions, omissions, and changes may be
made without departing from the spirit thereof. Accordingly, it is
intended that the scope of the present invention be limited solely
by the scope of the following claims, including equivalents
thereof.
* * * * *